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Computational insights into the first branching point in porphyrin biosynthesis: decarboxylation of ring D in URO–III by Uroporphyrinogen–III Decarboxylase
University of Windsor, Windsor, ON, N9B 3P4, Canada.
Örebro University, School of Science and Technology. (Biofysikalisk kemi)
University of Windsor, Windsor, ON, N9B 3P4, Canada.
National University of Ireland, Galway, University Road, Galway, Ireland.
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(English)Manuscript (preprint) (Other academic)
National Category
Physical Chemistry Theoretical Chemistry
Research subject
Physical Chemistry; Biochemistry
Identifiers
URN: urn:nbn:se:oru:diva-9950OAI: oai:DiVA.org:oru-9950DiVA: diva2:303425
Available from: 2010-03-12 Created: 2010-03-10 Last updated: 2011-04-28Bibliographically approved
In thesis
1. 5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
Open this publication in new window or tab >>5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. 76 p.
Series
Örebro Studies in Life Science, 6
Keyword
5-Aminolevulinic acid, tautomerization, PDT, DFT, MM, QM/MM, Porphobilinogen synthase, Uroporphyrinogen III decarboxylase, membrane penetration, enzyme mechanism
National Category
Physical Chemistry Theoretical Chemistry Theoretical Chemistry
Research subject
Physical Chemistry; Biochemistry
Identifiers
urn:nbn:se:oru:diva-9951 (URN)978-91-7668-718-5 (ISBN)
Public defence
2010-04-28, Hörsal M, Musikhögskolan, Örebro Universitet, Örebro, 10:15 (English)
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Supervisors
Available from: 2010-03-17 Created: 2010-03-10 Last updated: 2011-04-27Bibliographically approved

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Citation style
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